The pancreas functions as an exocrine gland which secretes digestive enzymes such as pancreatic lipase, trypsin, elastase and pancreatic amylase as well as an endocrine gland which secretes pancreatic hormones such as glucagon, insulin, somatostatin and pancreatic polypeptide (PP). Ghrelin has been known as a stomach hormone and in recent years, it has been reported that ghrelin is also secreted by cells in the pancreas. The pancreatic hormones are produced by pancreas islets that are cell cluster composed of four types of cells: α cells, β cells, δ cells and PP cells in the pancreas.
Insulin plays important roles in promoting glucose utilization, protein synthesis and production and storage of neutral fats, lowering blood glucose level as well as maintaining blood glucose within a normal range. Glucagon is a hyperglycemic hormone that functions via hepatic glycogenolysis or gluconeogenesis, and plays an important role in regulating sugar metabolism along with insulin. Somatostatin acts via a somatostatin receptor and suppresses secretion of various hormones such as glucagon and insulin in the pancreas. PP has been known as a satiety factor that is secreted from the cells in the islets of Langerhans in response to food intake, and suppresses the food intake and suppresses body weight gain. Ghrelin stimulates food intake and increases body weight by lowering fat oxidation.
Diabetes is a disease developed by insufficient secretion of insulin or insufficient response to insulin. Once it is developed, the disease is difficult to be cured completely. Diabetes is roughly classified into two types: type 1 diabetes mellitus which is an insulin-dependent diabetes, and type 2 diabetes mellitus which is a non-insulin-dependent diabetes.
Type 2 diabetes mellitus is a chronic disease begins with acquisition of insulin resistance, and is thought to be a type of diabetes whose onset mechanisms involve lifestyle habits such as obesity due to overeating or lack of exercise and stress. Type 2 diabetes mellitus is often developed in the middle-aged and elderly people, and many of patients with diabetes are affected with type 2 diabetes mellitus.
On the other hand, type 1 diabetes mellitus is a disease caused by destruction of β cells (insulin-producing cells) by, for example, autoimmune diseases and viral infections, which obstruct secretion of insulin in the body. Type 1 diabetes mellitus is mainly treated by a symptomatic therapy, i.e. by insulin administration. Pancreas transplantation or pancreatic islet transplantation is also employed so that the blood glucose level which continuously fluctuates in the body of the patient can become automatically controlled and the burden on the patients is reduced. Pancreas or pancreatic islet transplantation can effectively control the blood glucose level of the patient within the normal range. However, sufficient number of the organs that can be used for transplantation is not available. In addition, the patient who received the transplantation needs to take immunosuppressants for entire life to avoid immunorejection to a graft. Immunosuppressants may cause problems of infections or side effects.
A strategy including inducing insulin-producing cell in vitro from cells derived from a patient, and transplanting the induced cells into the patient has been proposed and studied. Insulin-producing cells can be obtained, for example, by obtaining cells from the epithelium of the pancreatic duct of a patient and differentiating the cells in vitro into insulin-producing cells.
Insulin-producing cells may also be obtained from pluripotent stem cells such as embryonic stem (ES) cells or induced pluripotent stem (iPS) cells by inducing differentiation of the cells into insulin-producing cells with an activin and retinoic acid (RA) (Patent Literature 1, and Non-Patent Literatures 1 to 5). Further, insulin-generating cells may also be generated by introducing PDX1 into pluripotent stem cells and culturing the cells (Patent Literature 2 and Patent Literature 3) as well as by culturing the pluripotent stem cells in the presence of suitably combined small molecule compounds (Patent Literature 4 and Non-Patent Literature 6). However, it has not been reported that any of the in vitro generated insulin-producing cells could successfully developed glucose responsiveness in a living body. On the other hand, it has been reported that pancreas precursor cells were generated and the cells secreted insulin depending on the glucose level when transplanted into a living body (Non-Patent Literatures 7 and 8).